Skeletal muscles are capable of adaptation in response to endurance training, by changing its fiber type composition, mitochondrial content and capillary densities, hence the functional properties. Orchestrated signal transduction from neuromuscular activity to gene regulatory machinery is responsible for the adaptive changes in the skeletal muscle. We have obtained preliminary results suggesting the importance of the p38 MARK pathway in endurance exercise-induced expression of peroxisome proliferator-activated receptor y co-activator-1a (PGC-1alpha) via myocyte enhancer factor 2 (MEF2) and activating transcription factor 2 (ATF2). Taken together with previous findings in the role PGC-1a in control of mitochondrial biogenesis and fiber specialization, we hypothesize that endurance exercise mediated-activation of p38 MAPK pathway induces transcriptional up-regulation of the PGC-1alpha gene and skeletal muscle adaptation. Our long-term objective is to define the signaling and molecular mechanisms for skeletal muscle adaptation in response to endurance exercise. The specific aims of this grant proposal are to: 1. Determine whether activation of the p38 MAPK pathway is obligatory to contractile activity-induced skeletal muscle adaptation. 2. Ascertain whether overexpression of a dominant negative form of p38p in skeletal muscle negates contractile activity-induced mitochondrial biogenesis and llb-to-lla fiber type switching. 3. Determine whether activation of the p38 MAPK pathway is sufficient to induce skeletal muscle mitochondrial biogenesis and fast-to-slow fiber type switching in transgenic mice. 4. Define the sequence elements and transcription factor-promoter interactions that are required for contractile activity-induced PGC-1a promoter activity in intact skeletal muscle of living mice using real-time bioluminescence imaging analysis. We plan to use both gain-of-function and loss-of-funtion genetic approaches in well-established endurance exercise model in vivo to investigate the regulation of the PGC-1a gene and the importance of the p38 pathway in exercise-induced skeletal muscle adaptation. Since many chronic diseases, such as coronary heart diseases, obesity, type 2 diabetes, and certain types of cancer, are attributable to physical inactivity and skeletal muscle disorders, and since regular exercise has significant positive effects on all of these diseases with no or little side effects, understanding the cellular and molecular mechanism of skeletal muscle adaptation will not only provide information to guide the correct and efficient use of regular exercise training for preventing and treating the diseases, but also facilitate discovery of new therapeutic drugs to combat the diseases